Nitric oxide donors and pharmaceutical compositions containing them

ABSTRACT

The present invention provides a compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound is a) a compound containing one or more sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO 2  group; b) a 5-membered ring heterocyclic compound containing a sulfur atom and a nitrogen atom, which ring is substituted by one or more substituents bearing a terminal —ONO 2  group; c) a 5-membered ring compound containing two conjugate S-atoms, which ring is linked to one or more substituents bearing a terminal —ONO 2  group; or d) a compound containing an acyclic —S—S group, linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO 2  group. The present invention further provides pharmaceutical compositions comprising one or more of said compounds as an active ingredient.

CONTINUING APPLICATION DATA

This application is a Divisional Application of U.S. Ser. No.09/381,303, filed Dec. 30, 1999, now U.S. Pat. No. 6,369,071incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to nitric oxide donors containing at leastone sulfhydryl group or a group capable of being converted in-vivo to asulfhydryl group, and at least one nitric oxide donor group. The novelcompounds are effective substitutes for existing tolerance-inducingorganic or inorganic nitric oxide donors.

BACKGROUND OF THE INVENTION

For over a century, the nitric oxide (NO) donor nitroglycerin (GTN) hasbeen the mainstay in the treatment of angina and related heart diseases.However, the existing mechanisms proposing the mediation of GTN actionby free NO, intracellular or extracellular S-nitrosothiol formation andsubsequent activation of guanylyl cyclase (GC), as well as thosedescribing GTN tolerance, have become increasingly controversial. Thephenomenon of tolerance to GTN, however, is of special clinicalimportance. In fact, early tolerance to the anti-anginal effects of thedrug is the major drawback of nitrate therapy, especially during acutemyocardial infarction. This is particularly important since alternativenon-tolerance inducing agents have not yet been developed tosuccessfully replace therapy with GTN.

Based on accumulating evidence, Applicant hypothesized that GTN maydirectly interact with SH-group/s located on its target enzyme (GC)resulting in its S-nitrosylation and activation. However, subsequentauto-oxidation (disulfide formation) of these SH-groups renders theenzyme inert towards farther reaction with GIN, resulting in tolerancedevelopment.

Additionally, evidence has recently been provided to support aninvolvement of the superoxide anion in the mechanism/s underlying GTNtolerance and cross-tolerance. According to these reports, increasedproduction of superoxide anion was found to accompany tolerancedevelopment to GTN in vascular tissue. Treatment with superoxidedismutase (SOD) significantly enhanced relaxation of control andtolerant vascular tissue to GTN and other exogenous and endogenousvasodilators.

While the precise mechanism for the vasorelaxant effect of GTN isunknown, a consensus exists regarding the primary involvement of cGMP inmediating the nitrate-induced relaxation. However, the roles ofsulfhydryl groups [reduced glutathione (GSH) and cysteine (Cys)] and ofvarious enzymes in the bioconversion of GIN and subsequent activation ofguanylyl cyclase (GC) leading to relaxation have become increasinglycontroversial. Cysteine was found to be the specific sulfhydryl requiredfor activation of soluble coronary arterial GC and to be the only one ofseveral sulfhydryl to react non enzymatically with GTN at physiologic pHresulting in formation of S-nitrosocysteine. Since S-nitrosothiols wereshown to be potent activators of GC, S-nitrosocysteine/thiols wereproposed as the intracellular mediators of organic nitrate-inducedvasorelaxation. Additionally, N-acetylcysteine (NAC, an immediate donorof Cys thereby increasing GSH) was reported to potentiate GTN activityin vitro and in vivo. The enhanced reaction of thiols with GTN in plasmaand blood versus buffer suggested that activation of GC by GTN may bemediated via extracellular formation of S-nitrosothiol/s. In either case(intra- or extracellular S-nitrosothiol formation), this associationbetween sulfhydryls and GTN activity has long been recognized asevidence for the “thiol depletion hypothesis”. However, recent studiesby the Applicant and those of Boesgard et al. revealed a dissociationbetween tissue thiol content (measured as Cys and GSH) and nitratetolerance in vivo.

In vitro inhibitory studies provide indirect support for the involvementof enzymes m GTN bioactivation [glutathione S-transferase (GST) andcytochrome P-450 (P-450)]. However, in view of several other reportssuggesting the lack of any significant role of GST and P-450 in GTNbioactivation, the reduced bioactivation of GTN is unlikely to be themain factor underlying nitrate tolerance in vivo. In fact, reduced cGMPproduction was also shown to follow exposure of vascular preparation todirect NO-donors, for which no definitive metabolic pathway has beenreported.

Furthermore, Applicant has recently presented in vivo evidence excludingthe involvement of any particular metabolic pathway since reduced cGMPwas also shown to follow treatment with S-alkylating agents in theabsence of GTN.

Heart disease is the leading cause of death in Western society and israpidly approaching this leading position worldwide. Ischemic heartdisease is the most common heart disease. For over a century,nitroglycerin and other organic nitrates have been used for thetreatment of various types of myocardial ischemia, including acutemyocardial infarction (AMI) and as adjuncts in the treatment of otherheart diseases (congestive heart failure and resistant hypertension).Chronic prophylaxis and acute treatment are necessary to preventcomplications of ischemic heart disease with potential fatal outcomes(˜25% death for AMI). Tolerance to the anti-ischemic effect of thesedrugs is, by far, the most serious drawback of therapy with currentlyavailable organic nitrates. The compounds proposed in this applicationconstitute a novel approach to overcome tolerance.

SUMMARY OF THE INVENTION

The present invention provides a compound containing at least onesulfhydryl group and at least one NO donor group, wherein said compoundis a) a compound containing one or more sulfhydryl groups linked to atleast one aromatic ring or a heteroaromatic ring with a nitrogen in thering structure, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group; b) a 5-membered ring heterocycliccompound containing a sulfur atom and a nitrogen atom, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group;c) a 5-membered ring compound containing two conjugate S-atoms, whichring is linked to one or more substituents bearing a terminal —ONO₂group; or d) a compound containing an acyclic —S—S group, linked to atleast one aromatic ring or a heteroaromatic ring with a nitrogen in thering structure, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group.

In one embodiment, the compound is:

In another embodiment, the compound is:

The present invention further provides a pharmaceutical compositioncomprising a) as an active ingredient at least one compound containingat least one sulfhydryl group and at least one NO donor group, whereinsaid compound is 1) a compound containing one or more sulfhydryl groupslinked to at least one aromatic ring or a heteroaromatic ring with anitrogen in the ring structure, which ring is substituted by one or moresubstituents bearing a terminal —ONO₂ group; 2) a 5-membered ringheterocyclic compound containing a sulfur atom and a nitrogen atom,which ring is substituted by one or more substituents bearing a terminal—ONO₂ group; 3) a 5-membered ring compound containing two conjugateS-atoms, which ring is linked to one or more substituents bearing aterminal —ONO₂ group; or 4) a compound containing an acyclic —S—S group,linked to at least one aromatic ring or a heteroaromatic ring with anitrogen in the ring structure, which ring is substituted by one or moresubstituents bearing a terminal —ONO₂ group; and b) a pharmaceuticallyacceptable carrier.

In one embodiment, the active ingredient is:

In another embodiment, the active ingredient is:

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention provides a compound containing at least onesulfhydryl group and at least one NO donor group, wherein said compoundis a) a compound containing one or more sulfhydryl groups linked to atleast one aromatic ring or a heteroaromatic ring with a nitrogen in thering structure, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group; b) a 5-membered ring heterocycliccompound containing a sulfur atom and a nitrogen atom, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group;c) a 5-membered ring compound containing two conjugate S-atoms, whichring is linked to one or more substituents bearing a terminal —ONO₂group; or d) a compound containing an acyclic —S—S group, linked to atleast one aromatic ring or a heteroaromatic ring with a nitrogen in thering structure, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group. The present invention further providespharmaceutical compositions comprising one or more of said compounds asan active ingredient.

The compounds are in vivo nitric oxide donors and they contain at leastone sulfhydryl group. As defined herein, a sulfhydryl group is eitherpresent in the reduced —SH form, or is a group capable of beingconverted in-vivo to a sulfhydryl group. In one embodiment, thecompounds contain a sulfhydryl group in the reduced —SH form. In anotherembodiment, the compounds contain a group capable of being convertedin-vivo to a sulfhydryl group. Suitable groups which are capable ofbeing converted in-vivo to a sulfhydryl group are illustrated in thefollowing embodiments: In one embodiment, the sulfhydryl group is in theoxidized —S—S disulfide form. In another embodiment, the sulfhydryl ispresent in a separately protected form (acetyl, carbamyl or other). Inanother embodiment, the sulfhydryl is present as an atom in aheterocyclic compound. In cases where the compound contains twosulfhydryl groups, these can exist in the reduced (SH) or the oxidized(disulfide) form or in a protected form. However, each one of thecompounds can also be regarded as a parent pro-drug which is assumed toundergo metabolic reduction or cleavage to provide the free SH groupsin-vivo.

In one embodiment, the compound is a compound containing one or moresulfhydryl groups linked to at least one aromatic ring or aheteroaromatic ring with a nitrogen in the ring structure, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group.In another embodiment, the compound is a 5-membered ring heterocycliccompound containing a sulfur atom and a nitrogen atom, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group.In another embodiment, the compound is a 5-membered ring compoundcontaining two conjugate S-atoms, which ring is linked to one or moresubstituents bearing a terminal —ONO₂ group. In another embodiment thecompound is a compound containing an acyclic —S—S group, linked to atleast one aromatic ring or a heteroaromatic ring with a nitrogen in thering structure, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group.

In accordance with an alternative embodiment of the present invention,the compound is a 6-membered ring compound containing two conjugateS-atoms which is substituted by one or more —ONO₂ groups or linked toone or more substituents bearing a terminal —ONO₂ group. In anotherembodiment the compound is a 6-membered ring compound containing 2conjugate S-atoms which is substituted by one or more —ONO₂ groups orlinked to one or more substituents bearing a terminal —ONO₂ group,wherein said 6-membered ring is conjugated to at least one carbocyclicaromatic nucleus or at least one pyridine nucleus. In anotherembodiment, the compound is a compound having an S—S group in an openconfiguration linked to one or more —ONO₂ groups or linked to one ormore substituents bearing a terminal —ONO₂ group.

In one embodiment, the compound is:

In another embodiment, the compound is:

All of the above compounds are such that they will undergo in vivometabolic cleavage to provide free —SH groups.

According to this invention, whenever a compound exists in the acidform, the term “acid” should also be understood to include thecorresponding acid halide, salts with pharmacologically acceptablealkali metal (including alkaline earth metal and ammonium bases), estersand amides. Moreover, the alcohol or the amines used to form thecorresponding ester and amides of the acid can also bear a nitrateester.

The present invention further provides a pharmaceutical composition forthe treatment of disorders where nitric oxide donors are indicated,comprising a) as an active ingredient at least one compound containingat least one sulfhydryl group and at least one NO donor group, whereinsaid compound is 1) a compound containing one or more sulfhydryl groupslinked to at least one aromatic ring or a heteroaromatic ring with anitrogen in the ring structure, which ring is substituted by one or moresubstituents bearing a terminal —ONO₂ group; 2) a 5-membered ringheterocyclic compound containing a sulfur atom and a nitrogen atom,which ring is substituted by one or more substituents bearing a terminal—ONO₂ group; 3) a 5-membered ring compound containing two conjugateS-atoms, which ring is linked to one or more substituents bearing aterminal —ONO₂ group; or 4) a compound containing an acyclic —S—S group,linked to at least one aromatic ring or a heteroaromatic ring with anitrogen in the ring structure, which ring is substituted by one or moresubstituents bearing a terminal —ONO₂ group; and b) a pharmaceuticallyacceptable carrier.

In one embodiment, the active ingredient is a compound containing one ormore sulfhydryl groups linked to at least one aromatic ring or aheteroaromatic ring with a nitrogen in the ring structure, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group.In another embodiment, the active ingredient is a 5-membered ringheterocyclic compound containing a sulfur atom and a nitrogen atom,which ring is substituted by one or more substituents bearing a terminal—ONO₂ group. In another embodiment, the active ingredient is a5-membered ring compound containing two conjugate S-atoms, which ring islinked to one or more substituents bearing a terminal —ONO₂ group. Inanother embodiment the active ingredient is a compound containing anacyclic —S—S group, linked to at least one aromatic ring or aheteroaromatic ring with a nitrogen in the ring structure, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group.

In accordance with an alternative embodiment, the active ingredient is a6-membered ring compound containing two conjugate S-atoms which issubstituted by one or more —ONO₂ groups or linked to one or moresubstituents bearing a terminal —ONO₂ group. In another embodiment theactive ingredient is a 6-membered ring compound containing 2 conjugateS-atoms which is substituted by one or more —ONO₂ groups or linked toone or more substituents bearing a terminal —ONO₂ group, wherein said6-membered ring is conjugated to at least one carbocyclic aromaticnucleus or at least one pyridine nucleus.

In another embodiment, the active ingredient is a compound having an S—Sgroup in an open configuration linked to one or more —ONO₂ groups orlinked to one or more substituents bearing a terminal —ONO₂ group.

In one embodiment, the active ingredient is

In another embodiment, the active ingredient is:

Because of their SH-content (radical scavenging and anti-oxidantproperties), these compounds may also be applied for other pathologies.Thus, considering their promising chemical and pharmacologicalcharacteristics and the ever-increasing demand for better therapy forheart diseases, significant potential exists for compounds of this typeto become the next generation of vasodilators. This is especially trueconcerning the considerable amount of recent evidence indicating theinvolvement of nitric oxide, reactive oxygen species and thiols in avariety of conditions, the pathogenesis of as well as the treatment forwhich have not been fully resolved. These include (but are not limitedto): atherosclerosis, pulmonary and systemic hypertension, asthma andother related respiratory diseases, trauma, shock, neurotoxicity,neurodegenerative and neurologic disorders, including those involvinglearning, memory, olfaction and nociception, Huntington, Alzheimer andParkinson's diseases, multiple sclerosis and convulsive (seizure)disorders, AIDS-related disorders (i.e. dementia), disorders of gastricacid and other secretory and peristaltic functions of the alimentarysystem, drug and disease-induced neuropathy and nephropathy,pathological and premature uterine contractions, cellular defenseimpairment, and insulin-resistance in glucose intolerance and diabetesmellitus, pregnancy-induced hypertension, chemotaxis and phagocyticimpairment in immunological disorders, cerebrovascular diseases,aggregation disorders, perile erection and treatment of male impotence.

Although the exact mechanisms defining organic nitrates and other nitricoxide donors' action and tolerance are not completely elucidated, theprimary roles of nitric oxide (being their first messenger) and cGMP(the second messenger) in mediating vasorelaxation are universallyaccepted. Applicant has demonstrated herein, utilizing example compounds1 to 6 from page 14, that, unlike currently available organic andinorganic nitrates, these compounds possess equipotent or ever superiorvasorelaxant activity. Moreover, using cGMP measurements both inextended periods of exposure to the drug when used, for example, innitroglycerin-equimolar dosing regimens for which tolerance to thecGMP-inducing activity of nitroglycerin has been documented under thesame experimental conditions (see table on page 30).

For the preparation of pharmaceutical compositions, the novel compoundsare mixed in the usual way with appropriate pharmaceutical carriersubstances, aroma, flavoring and coloring materials and formed, forexample, into tablets or dragees of immediate or sustained release or,with additions of appropriate adjuvants, for example water or an oilsuch as olive or other oil, are suspended or dispersed or dissolved.

The compounds or the pharmaceutical composition thereof can beadministered orally (including the sublingual and buccal routes) or viaan injectable form (including the subcutaneous, intramuscular,intraperitoneal and the parenteral routes). Other routes ofadministration such as aerosols and dermal preparations are also to beconsidered. As injection medium, water is preferably used which containsthe stabilizing agents, solubilizing agents and/or buffers usuallyutilized in the preparation of solutions for injection. Such additivesinclude, for example, tartarate and borate buffers, ethanol, ethyleneand propylene glycols, glycerol, dimethyl sulphoxide, complex formers(i.e., ethylenediamine tetraacetic acid), high molecular weight polymers(such as liquid polyethylene oxide) for viscosity regulation andpolyethylene derivatives of sorbit anhydrides. Solid carrier materialsinclude, for example, starch, lactose, manitol, methyl cellulose, talc,highly dispersed silicic acid, high molecular weight polymers (i.e.,polyethylene glycol). Compositions suitable for oral administration (asdefined above) can, if necessary, contain flavoring and sweeteningagents.

The synthesis of the novel compounds was carried out utilizingconventional organic synthetic methods. The following examples are givenfor the purpose of illustrating the present invention:

EXAMPLE 1 trans-1,2-Dinitrato-4,5-dithiane (Compound 1. Page 14)

The compound was easily synthesized utilizing the commercially availableprecursor trans-1,2-dihydroxy-4,5-dithiane. 0.5 g of the precursor wasadded portionwise to chilled (−5° C.) 1:1 mixture of fuming nitricsulfuric acids. Upon completion of the addition, the ice/salt bath wasremoved and the mixture brought to room temperature. This mixture wasadded dropwise to a cooled mixture of dry diethylether:acetonitrile:water (70:20:10) with vigorous stirring. The loweraqueous phase was separated and extracted twice with diethyl ether. Thecombined organic extracts were washed twice with water and once withcold 1% sodium carbonate solution. The organic layer was dried overmagnesium sulfate and evaporated to near dryness under reduced pressure.The residual oil was loaded on a silica column and separated afterelution with hexane. Evaporation under reduced pressure of the eluateyielded a yellowish oil (0.56 g) with analytical data consistent withthe structure of trans-1,2-dinitrato4,5-dithiane.

EXAMPLE 2 2,2′-Dithiodiethanol-dinitrate (Compound 2, Page 14)

The compound was synthesized in a similar fashion to compound 1 aboveusing the commercially available precursor 2,2′-dithiodiethanol as thestarting material. The precursor was nitrated and separated as aboveyielding the title compound 2,2′-dithiodiethanol-dinitrate.

EXAMPLE 3 1,1-Diemethanol-dinitrate-3,4-dithiane (Compound 3, Page 14)

This compound was synthesized by bishydroxymethylation of diethylmalonate followed by thiolation of the hydroxyl groups (via the halideintermediate). The resulting 1,1-dicarboxy-3,4-dithiane was reduced byborane (catechol borane solution) to the corresponding1,1-diemethanol-3,4-dithiane. Direct nitration of this latterintermediate yielded the title compound 1,1-diemethanolinitrate-3,4-dithiane.

EXAMPLE 4 1,1′-Bisthiomethyl-3,4-dihydroxy-cyclohexane-dinitrate ester(Compound 4, Page 14)

This compound was synthesized by thiolation of the dichlorideintermediate of the commercially available1,1′-bishydroxymethyl-3-cyclohexene. Oxidation of the double bond eitherby hydrogen peroxide/asmium tetroxide to generate the cis-diol or by aperacid/formic acid mixture to generate the trans-diol followed bynitration of the diol will generate the corresponding (cis or trans)form of the title compound.

EXAMPLE 5 Thioctyl Alcohol Nitrate Ester (Compound 5, Page 14)

This compound was synthesized in a high yield process utilizing Thioctylacid as the precursor. Following reduction of the acid (or its methyl orethyl ester) by catechol borane solution, the resulting thioctyl alcoholwas separated and mitrated as described above to yield the titlecompound.

EXAMPLE 6 1,2-Dihydroxy-dinitrate-6,8-dithiane (Compound 6, Page 14)

2-Hydroxy lipoic (thioctic) acid was synthesized from thioctic acid viathe 2-bromo derivative. This intermediate was reduced via borane toyield the direct precursor 1,2-dihydroxy-6,8-dithiane which, uponnitration as described above, yielded the title compound.

Experimental Report

Representative for the new compounds, the vasorelaxant activities(measured as the ability of the tested drug to induce an increase invascular cGMP) of the example compounds 1 to 6 were determined andcompared to activity of nitroglycerin under the same experimentalconditions following single and sustained exposure of rats to thecompound.

For this purpose the compound to be tested was administered, in eachcase, to 8 male Sprague-Dawley rats (300-400 g) before and after an 18hr continuous intravenous infusion of the compound. The 18 hr continuousinfusion period was determined based on existing data demonstrating thedevelopment of tolerance to the drug effect in the case ofnitroglycerin. The existence of tolerance to the drug is demonstrated bythe inability of the drug to attain 50% or more of the cGMP valuesmeasured in the vascular tissue after dosing of the drug to preciouslytreated animals as compared to controls (non-treated or vehicle-treatedanimals). After drug administration (i.v. push), the rat was sacrificed,the aorta immediately removed and processed for cGMP measurement as hasbeen described in detail by us. All of the tested new compounds wereutilized in nitroglycerin equimolar doses, either before of after the“tolerance” induction period.

The following table summarizes the results obtained followingadministration of either nitroglycerin or the tested compounds beforeand after an 18 hr continuous exposure to the same compound:

cGMP (pmol/g tissue) Tested Compound Pre-infusion Post-infusionNitroglycerin 153 ± 13  68 ± 9** Compound 1 196 ± 14 189 ± 13* Compound2 169 ± 12 174 ± 13* Compound 3 171 ± 14 174 ± 16* Compound 4 149 ± 11169 ± 13* Compound 5 123 ± 13 113 ± 11* Compound 6 193 ± 17 179 ± 12***Significantly different from the pre-infusion values and denotestolerance. *Not significantly different from pre-infusion levels anddenotes the lack of tolerance.

Besides their expected superior vasorelaxant activity, these resultsclearly demonstrate that whereas tolerance to the cGMP-inducing activityof nitroglycerin developed early (18 hr) following its continuous invivo administration, no tolerance was observed to the cGMP-increasingeffects of the novel compounds under the same experimental conditionsused for the induction of in vivo tolerance. In fact, Applicant shows inpreliminary results that no tolerance to this cGMP-inducing effect ofthese novel SH-containing-NO-donors develops even after exposure of theanimals to the compounds for extended periods of time (i.e., not evenafter 168 hr of continuous intravenous infusions).

It will be understood that the compounds shown demonstrate the principleupon which this invention is based. Thus, the specification and examplesgiven in this application are illustrative but not limitative of thepresent invention and embodiments within the spirit and scope of theinvention will suggest themselves to those skilled in the art. Rather,the scope of the invention is defined by the claims which follow.

What is claimed is:
 1. A compound containing at least one sulfhydrylgroup and at least one NO donor group, wherein said compound is: acompound containing one or more sulfhydryl groups linked to at least onearomatic ring or a heteroaromatic ring with a nitrogen in the ringstructure, which ring is substituted by one or more substituents bearinga terminal —ONO₂ group; a 5-membered ring heterocyclic compoundcontaining a sulfur atom and a nitrogen atom, which ring is substitutedby one or more substituents bearing a terminal —ONO₂ group; a 5-memberedring compound containing two conjugate S-atoms, which ring is linked toone or more substituents bearing a terminal —ONO₂ group; or a compoundcontaining an acyclic —S—S group, linked to at least one aromatic ringor a heteroaromatic ring with a nitrogen in the ring structure, whichring is substituted by one or more substituents bearing a terminal —ONO₂group.
 2. A compound according to claim 1, wherein said compound is:


3. A compound according to claim 1, wherein said compound is:


4. A pharmaceutical composition comprising a) as an active ingredient atleast one compound containing at least one sulfhydryl group and at leastone NO donor group, wherein said compound is: a compound containing oneor more sulfhydryl groups linked to at least one aromatic ring or aheteroaromatic ring with a nitrogen in the ring structure, which ring issubstituted by one or more substituents bearing a terminal —ONO₂ group;a 5-membered ring heterocyclic compound containing a sulfur atom and anitrogen atom, which ring is substituted by one or more substituentsbearing a terminal —ONO₂ group; a 5-membered ring compound containingtwo conjugate S-atoms, which ring is linked to one or more substituentsbearing a terminal —ONO₂ group; or a compound containing an acyclic —S—Sgroup, linked to at least one aromatic ring or a heteroaromatic ringwith a nitrogen in the ring structure, which ring is substituted by oneor more substituents bearing a terminal —ONO₂ group; and b) apharmaceutically acceptable carrier.
 5. A composition according to claim4 wherein the active ingredient is:


6. A composition according to claim 4, wherein the active ingredient is: